The Challenge of Treating a Rare Syndrome
Kleine-Levin Syndrome (KLS), sometimes called “Sleeping Beauty syndrome,” is characterized by recurring episodes of severe hypersomnia, where affected individuals may sleep for up to 20 hours a day. These episodes are often accompanied by cognitive and behavioral disturbances, including confusion, derealization, apathy, and sometimes hyperphagia and hypersexuality. Between episodes, patients typically return to a normal state. The rarity of KLS and the unpredictable nature of its episodes have made it difficult to conduct large, randomized controlled trials (RCTs), meaning there is a lack of high-quality evidence to support a single standard of care. As a result, the pharmacological approach is largely based on observational studies, case reports, and symptom management.
Prophylactic Treatments to Prevent Episodes
For individuals with frequent or severe episodes, preventive treatment is often considered. The goal of prophylaxis is to reduce the frequency, duration, and intensity of attacks.
- Lithium: This mood-stabilizing medication is the most widely studied prophylactic treatment for KLS and is sometimes considered the closest thing to a “drug of choice” for prevention. A large, prospective, open-label study showed that lithium significantly reduced the frequency and duration of KLS episodes compared to no treatment. It is thought to work through neuroprotective and anti-inflammatory effects.
- Antiepileptic Drugs: Other mood stabilizers and antiepileptics have been used with varying success. Carbamazepine and valproate have shown benefits in some case reports, particularly in patients with co-occurring seizure disorders or specific symptoms. However, they are generally considered less efficacious than lithium.
Symptomatic Treatments During Episodes
Medications used during KLS episodes are aimed at managing specific symptoms, primarily the excessive daytime sleepiness. They do not typically affect the underlying syndrome or prevent future recurrences.
- Stimulants: Wake-promoting agents such as modafinil and methylphenidate are often prescribed to combat the debilitating sleepiness. While they can increase alertness, they may also worsen irritability and do little to improve the cognitive and behavioral disturbances associated with the episodes.
- Intravenous (IV) Steroids: For unusually long or severe episodes (typically lasting more than 30 days), a trial of IV corticosteroids may be considered. Some patients have shown a positive response, with the episode shortening, but this approach does not consistently work for everyone.
Emerging and Less Common Treatment Options
Recent years have seen case reports exploring the use of other medications, often based on novel hypotheses about the syndrome's pathology. These treatments are not standard and require further research.
- Clarithromycin: One case report detailed a short-term beneficial effect of the antibiotic clarithromycin, which has a GABA-A receptor antagonistic property, leading to a temporary reduction in sleepiness. However, its effectiveness dissipated over time, and the clinical usefulness of this finding is limited.
- Acetazolamide: Another case report described a patient who experienced a dramatic improvement in both frequency and severity of symptoms with acetazolamide, a carbonic anhydrase inhibitor often used for channelopathies. While impressive, this was a single case, and more evidence is needed.
Non-Pharmacological Management and Prognosis
Given the limitations of pharmacological options, a holistic and supportive approach is critical for managing KLS. This is especially true since the syndrome often resolves spontaneously after 8 to 14 years.
- Supportive Care: During an episode, the most effective strategy is providing a safe, comfortable, and supervised environment for the patient to rest.
- Trigger Avoidance: Between episodes, patients and caregivers should work to identify and avoid potential triggers, which can include infections, alcohol, stress, and sleep deprivation.
- Routine: Maintaining regular sleep-wake habits during asymptomatic periods can also be beneficial.
Comparison of Common KLS Treatments
| Feature | Lithium (Prophylactic) | Stimulants (Symptomatic) | Supportive Care |
|---|---|---|---|
| Primary Goal | Reduce episode frequency and duration | Increase wakefulness during episodes | Ensure safety and comfort during episodes |
| Typical Use | For patients with frequent, long, or severe episodes | During the episode to manage hypersomnia | Universally, as primary or adjunctive therapy |
| Effectiveness | Significant benefit in controlled studies for many patients | Marginally effective for sleepiness, ineffective for other symptoms | Crucial for overall patient safety and well-being |
| Side Effects | Tremor, increased thirst/urination, GI issues, subclinical hypothyroidism | Irritability, anxiety, appetite loss | None associated with the approach itself, but managing patient behavior is a challenge |
| Level of Evidence | Fair (based on large observational study) | Low (based on case reports and clinical experience) | High (standard clinical practice) |
Conclusion
While the search for a definitive answer to what is the drug of choice for Kleine-Levin syndrome continues, clinicians and patients currently rely on a combination of strategies tailored to individual symptoms. Lithium is the most established option for prophylaxis, showing promise in reducing the frequency and severity of episodes for many patients. However, it is not a cure, and a significant portion of patients may not respond well. Stimulants offer a short-term solution for managing the extreme sleepiness during episodes but do not address the cognitive or behavioral aspects. Given the syndrome's tendency to resolve spontaneously over time, supportive care is a cornerstone of management for all patients. Ongoing research into KLS, including functional imaging and genetic studies, continues to deepen our understanding and may lead to more targeted and effective treatments in the future. In the absence of a universal cure, a personalized, supportive, and medically monitored approach remains the standard for managing this challenging condition.
Visit the National Organization for Rare Disorders (NORD) to learn more about KLS.
